Centrosomes are cellular organelles that include two centrioles enclosed in a proteinaceous mass called the pericentriolar matrix (PCM). Centrosomes, by nucleating and organizing the cell's microtubular cytoskeleton, play a key role in regulating cell structure, directional cell migration and tissue polarity. Centrosomal defects, termed centrosome amplification (CA), can arise from various aberrant processes, including cell-cell fusion, centrosome fragmentation, de novo centriole formation, dysregulation of the canonical centrosome duplication cycle, and possibly cytokinesis failure. In addition to exhibiting numerical abnormalities, amplified centrosomes are oftentimes abnormal in structure, function, or localization within the cell.
While the mechanisms underlying centrosome amplification (CA) and their consequences are not entirely understood, CA is largely considered a hallmark of cancer cells, but a rare phenomenon in normal or benign tissue. CA is thought to play a key role in the development of cancer, and it is causally linked to chromosomal instability during tumor development and the generation of the genetic diversity that underlies other malignant phenotypes. Notably, CA occurs in pre-cancerous and pre-invasive lesions, suggesting that it may play an early, causal role in driving tumor progression and contributing to metastatic risk. CA is postulated to translate into a greater risk for initiation of malignant transformation, tumor progression and poor patient prognosis. CA has been detected in both solid and haematological cancers. For instance, CA has been detected in malignant human cells in a variety of tissues including breast, prostrate, lung, brain, colon, bladder, kidney, cervix, testis, ovary, liver, pancreas, head and neck, and blood.
Several methods and prediction tools are readily available in the field of oncology. These prediction tools are used to assist physicians, oncologists and cancer patients in calculating various components of cancer risk. The present methods also concern risk but are more focused on the risk of a benign tumor progressing to malignancy or the risk associated with a tumor diagnosed to be malignant (e.g., the risk of rapid tumor progression into metastasis, the risk of recurrence and poor outcomes in general for an individual patient). In many cases, present methods require a myriad of information depending on the cancer type. Moreover, it is becoming increasingly recognized that every cancer patient's disease is unique and only personalized medicine can yield the most optimal outcomes.
Typically, CA is not included in any of the tools for assessment of risk associated with a tumor even though amplified centrosomes have long been associated with more aggressive tumor characteristics. Most CA studies focus only on the numeric alterations as the key marker for CA and neglect to consider both numeric aberrations along with structural defects. A facile method of quantifying CA (both numerical and structural aspects of CA) reliably and accurately in various tumors is urgently needed to provide a foundation for centrosome status-based risk assessment. The present application addresses a need for better tools in assessing risk associated with tumors and providing adequate treatment therefore.